a phase 3 study assessing safety and efficacy of bedaquiline plus pa-824 plus linezolid in subjects with drug resistant pulmonary tuberculosis

Conditions: Pulmonary Tuberculosis

Summary: the purpose of this study is to evaluate the efficacy, safety, tolerability and pharmacokinetics of bedaquiline plus pa-824 plus linezolid after 6 months of treatment (option for 9 months for participants who remain culture positive at month 4) in participants with either pulmonary extensively drug resistant tuberculosis (xdr-tb), treatment intolerant or non-responsive multi-drug resistant tuberculosis (mdr-tb).

up to 200 male and female participants aged 14 and over with confirmed sputum positive for m.tb. in culture pulmonary xdr-tb, or with pulmonary mdr-tb with a documented intolerability or non-response to the best treatment available for 6 months or more will be enrolled. all participants will have up to a maximum of 9 days for screening, receive 6 months of treatment, and have followup visits performed 1 and 2 months after treatment completion and every 3 months after study treatment completion for 24 months. if a participant is culture positive or revert to being culture positive between month 4 and month 6 visits and their clinical condition suggests they may have ongoing tb infection, they may have treatment extended to 9 months (with 24 months of follow up) or be withdrawn from the study. participants who withdraw after \ 15 days of imp should return for an early withdrawal visit and follow-up visits at 3, 6 and 24 months after their last dose of imp to check for survival, saes and resolution of tb symptoms.

Eligibility criteria:
key inclusion criteria 1. provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian). 2. body weight of ≥35 kg (in light clothing and no shoes). 3. male or female, aged 14 years or above. 4. subjects with one of the following pulmonary tb conditions (who definitions prior to 2021): a. extensively drug resistant tuberculosis (xdr-tb) with i. documented culture positive (for m.tb.) results within 3 months prior to screening or m.tb. confirmed in sputum based on molecular test within 3 months prior to or at screening; ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening; b. multi-drug resistant tuberculosis (mdr-tb) documented by culture positive results (for m.tb.) within 3 months prior to or at screening with documented non-response to treatment with the best available regimen for 6 months or more prior to enrolment who in the opinion of the investigator have been adherent to treatment and will be adherent to study regimen; c. mdr-tb documented by culture positive (for m.tb.) results within 3 months prior to or at screening who are unable to continue second line drug regimen due to a documented intolerance to: i. pas, ethionamide, aminoglycosides or fluoroquinolones; ii. current treatment not listed above that renders subject eligible for the study in the investigator's opinion. 6. chest x-ray picture (taken within a year prior to screening) consistent with pulmonary tb in the opinion of the investigator. key exclusion criteria 1. karnofsky score \< 50 within 30 days prior to entry. 2. body mass index (bmi) \< 17 kg/m² 3. history of allergy or known hypersensitivity to any of the trial investigational medicinal products or related substances. 4. hiv infected subjects having a cd4+ count ≤ 50 cells/μl 5. having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational study that includes treatment with medicinal agents. subjects who are participating in observational studies or who are in a follow up period of a trial that included drug therapy may be considered for inclusion. 6. significant cardiac arrhythmia requiring medication. 7. subjects with the following at screening: 1. qtcf interval on ecg \>500 msec. 2. history of additional risk factors for torsade de pointes, (e.g., heart failure, hypokalemia, family history of long qt syndrome); 3. clinically significant ventricular arrhythmias; 4. subjects with other cardiac abnormalities that may place them at risk of arrhythmias must be discussed with the sponsor medical monitor before enrolment. such abnormalities include: evidence of ventricular pre-excitation (e.g., wolff parkinson white syndrome); electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; evidence of second or third degree heart block; intraventricular conduction delay with qrs duration more than 120 msec. 8. females who have a positive pregnancy test at screening or already known to be pregnant, breastfeeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. males planning to conceive a child during the study or within 6 months of cessation of treatment. 9. a peripheral neuropathy of grade 3 or 4, according to dmid (appendix 2). or, subjects with a grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the investigator. 10. concomitant use of monoamine oxidase inhibitors (maois) or prior use within 2 weeks of treatment assignment. 11. subjects with the following toxicities at screening as defined by the enhanced division of microbiology and infectious disease (dmid) adult toxicity table (november 2007): a. serum potassium less than the lower limit of normal for the laboratory; b. hemoglobin level grade 2 or greater (\ 3 x uln g. total bilirubin \> or = to 2xuln h. direct bilirubin \> uln i. serum creatinine level greater than 2 times upper limit of normal j. albumin \<32 g/l

Keywords: tuberculosis mdr-tb xdr-tb multi-drug resistant extensively drug resistant bedaquiline pa-824 linezolid tb pretomanid tmc-207 nix-tb